Lithium is a highly effective therapy for bipolar disorder (BPD), a chronic and disabling mental illness affecting millions of people in the US. Understanding the therapeutic action of lithium would provide important insight into the etiology and pathophysiology of BPD. The long-term goal ofthis project is to elucidate the mechanisms underlying the therapeutic action of lithium. The objective of this proposed research is to identify genes involved in the lithium-responsive neurological pathway using Drosophila genetics. Shudderer (Shu) is an X-linked dominant mutant of Drosophila that exhibits various neurological phenotypes, including uncoordinated movements, sporadically occurring jerks and anesthesia-induced seizure. Interestingly, many of these phenotypes are greatly suppressed by lithium using therapeutic concentrations. The rationale is that once the Shu gene is identified and genes functionally interacting with Shu are revealed, we expect to obtain novel clues to elucidate the lithium-responsive neurobiological processes. My recent studies have shown that the gene CanA-14F, encoding the catalytic A subunit of calcineurin, is involved in the manifestation ofthe Shu phenotypes. I also have identified several genomic regions in a large-scale deletion screen covering the entire 2nd and 3rd chromosomes, whose loss results in suppression ofthe mutant phenotypes. Based on these findings, I plan to accomplish the above objective by pursuing two specific aims, 1) Determine how misregulation of calcineurin causes the Shu mutant phenotypes and 2) Identify genes functionally interacting with Shu. For Aim-1, I will manipulate CanA-14F gene activity in a tissue- and developmental timing-specific manner using the UAS/GAL4 system to investigate its effect on the Shu phenotype. For Aim-2, smaller, molecularly defined deletions, mutations and transgenic RNAi lines will be introduced into the Shu mutant background to reduce the genomic regions to a managable area and identify the gene(s) responsible for suppression of the mutant phenotypes. The proposed research is significant, because studies of Shu are expected to provide novel knowledge of genetic components underlying the evolutionarily conserved lithium-responsive process in the nervous system, possibly leading to the development of novel and improved therapies for BPD. Lithium is an effective drug for bipolar disorder (BPD), but little is known about the mechanisms underlying its therapeutic action. The proposed studies are designed to identify genes involved in the evolutionarily conserved lithium-responsive processes in the nervous system to aid in the development of improved therapies for BPD.